Posttraumatic stress disorder (PTSD) has been recognized as one of the signature invisible wounds of the recent conflicts in Iraq/Afghanistan. PTSD is a debilitating serious condition that poses a huge burden on healthcare providers and patient's families, and to date remains untreatable. Given the large number of returning combat veterans and the prevalence of PTSD amongst this group (>20%), new perspectives on biological responses of PTSD are desperately needed. We have identified abnormalities in lipids and signaling pathways in blood samples of active duty soldiers with PTSD. Significant reductions in monounsaturated fatty acids, ether- phospholipids, docosahexaenoic acid containing lysophosphatidylcholine, sphingomyelin, and RXR/PPAR signaling were observed. These biological influences have been little explored in PTSD. Lipids are pleiotropic in action and have a variety of roles in regulating cardiovascular, autonomic, neuroendocrine and neuroplasticity functions, all involved in PTSD pathophysiology. We hypothesize that these molecules and their related pathways may play a significant role towards PTSD pathobiology and represent targets for further validation. We recently pioneered the characterization of long-term behavioral, physiological and neuroendocrine consequences after trauma in a PTSD-like mouse model, with a focus on developing relevant models to use in subsequent therapeutic discovery. We have generated preliminary data showing similar changes in our lipid related targets in the brain tissue of our mouse PTSD model. In this study we will examine longitudinal changes in our identified targets in a larger cohort of mice, to confirm their modulation in plasma and/or brain tissue in response to stress. We will also examine key related pathways to which the molecular candidates likely belong by probing for bioactive downstream lipids, enzymes, important rate limiting steps in biosynthesis and related receptors where relevant. We will confirm the clinical relevance of our findings by investigating the same targets and pathways in brain tissue from autopsied PTSD cases, and will then evaluate in vivo target engagement for 8 compounds that modulate the identified molecular targets in a short-term treatment paradigm. The two most potent novel therapeutic strategies will then be investigated in a chronic treatment paradigm, individually and as a combination therapy (given the multifaceted nature of PTSD pathophysiology) in our mouse model. The overarching goal of this study is to provide critical information on potential therapeutic targets for PTSD along with preliminary data to further evaluate and develop these targets and compounds as novel approaches to mitigate the effects of PTSD. Together, we believe that this will contribute to much needed PTSD focused treatments that can be translated into clinical trials.